Selected Articles from This Issue

Abstract

Interleukin-15 (IL-15) regulates the generation, persistence, and differentiation of natural killer (NK) and CD8 T cells. To expand its role in cancer immunotherapy, Chen and colleagues designed a multitumor model treated with the combination of intratumoral anti-CD40, parenteral IL-15 and anti-PD-1. Anti-CD40 given intratumorally not only reduced dosing requirements and toxicity, but it also stimulated the antitumor activity of the distal tumors, suggestive of an abscopal effect. IL-15 with intratumoral anti-CD40 was additive/synergistic, and the inclusion of the anti-PD-1 was additive to the combination. Thus, this treatment shows promise for patients with solid tumors or resistance to anti-PD-1 therapy.Cancer-associated fibroblasts (CAF) are a heterogenous cell population with a complex immunoregulatory role, which has not been well defined in head and neck squamous cell carcinoma (HNSCC). Leveraging protein activity inference tools to analyze scRNA-sequencing of HNSCC patients, pre- and post-nivolumab, Obradovic and colleagues identified distinct subpopulations of head and neck CAF (HNCAF). Enrichment of a T-cell stimulating population (tsCAF) was found to associate with treatment response and ex vivo assays confirmed this CAF subset reduces CD8 T-cell exhaustion. Analysis of an independent HNSCC cohort treated with pembrolizumab validated this tsCAF subset as a potential biomarker of response.Approximately 30% of MSI-H/dMMR tumors do not respond to immune checkpoint inhibitors (ICI), highlighting the importance of identifying predictive biomarkers or molecular profiling correlated with resistance to these agents. Here, Chida and colleagues performed transcriptomic profiling of MSI-H/dMMR gastrointestinal tumors treated with PD-1 blockade. The study revealed that nonresponders had the enrichment of epithelial mesenchymal transition, angiogenesis, hypoxia, mTORC1, KRAS, Wnt/β-catenin, TGF-β, and various metabolism-related signaling pathways, which have been associated with an immunosuppressive tumor microenvironment. Meanwhile, the IFN-γ pathway was upregulated in responders. High expression of VEGF-A might predict a negative response to ICI in this population.Acral melanoma is a rare subtype of melanoma that arises on non-sun exposed skin of the hands, feet, and nailbeds. Patients with acral melanoma have lower response rates to immunotherapy than those with nonacral cutaneous melanoma, suggesting unique microenvironmental features. In their study, Li and colleagues performed comprehensive single cell analysis of a cohort of acral melanoma specimens and found them to harbor fewer effector CD8 T cells and NK cells and a complete absence of γδ T cells compared to non-acral cutaneous melanoma. VISTA, TIGIT, and adenosine signaling were identified as targetable immune checkpoints in acral melanoma.